L12 Neuroendocrine Hormones Flashcards
The endocrine system regulates many of the body’s activities:
growth; reproduction; adaption to stress; immunity; metabolic activity; glucose homeostasis; circulatory volume; Ca2+ homeostasis
Endocrine activities are produced by endogenous chemical messengers, called _____ which are secreted from endocrine glands.
endocrine hormones
Several major hormones are members of the neuroendocrine system, in which hormone release is regulated by the_____
brain
Parts of the endocrine system
The female ovaries, male testes, and pituitary, thyroid, and adrenal glands are major constituents of the endocrine system
Neuroendocrine anatomy
- [pictures on slides] pituitary glands underneath brain. It is attached to the hypothalamus via a stalk.
- Mainly the hypothalamus and the pituitary gland
Releasing factors/peptides
GnRH; GHRH; TRH; CRH Somatostatin (GIR)
Tropic hormones
ACTH; GH; FSH; LH; TSH; PRL
ACTH
- Adrenocorticotropic hormone (ACTH)
- tropic hormone produced by the A.pituitary.
- The hypothalamic-pituitary axis controls it.
- ACTH regulates cortisol and androgen production. (glucocorticoids and mineralcorticoids)
GH
- growth hormone
- growth promotion: lipids and carbohydrate metabolism
FSH + LH
- growth of reproductive system
- sex hormones
TSH
- Thyroid Stimulating Hormone
- produced by the pituitary gland.
- regulate (stimulate) production of thyroid hormones by the thyroid gland.
PL
- prolactin
- milk production
Neuroendocrine system is diagram
Neural tissue
↓ RF
Endocrine system
↓ blood (tropic hormone)
Endocrine tissue/ gland
↓ blood (effector hormone). ⥀ negative feedback
Target organs/tissues
↓
Physiological response
Drugs (pharmacology) vs hormone
{slides}
Thyroxine hormone (gland/effect/release)
- thyroid
- Brain development; digestion; increase metabolic activity
- TSH
- part of hypothalamic pituitary axis
Insulin-like growth factor (gland/effect/release)
- liver
- Growth and metabolism
- GH
- hypothalamic pituitary axis
Cortisol (gland/effect/release)
- Adrenals
- Adaptation to stress; immunomodulation
- ACTH
- part of hypothalamic pituitary axis
Sec steroids (gland/effect/release)
- Testes; ovaries; placenta
- Reproduction; secual characteristics
- LH, FSH
- hypothalamic pituitary axis
Insulin (gland/effect/release)
- pancreas
- availability of glucose to cells
- blood glucose levels
Hormone release is stimulated by hypothalamic _____ ____ and pituitary trophic hormones, which regulate effector hormone_____ and actions
releasing factors
production
Neuroendocrine system: example of hormone release
Physiologic input from the brain
↓
Hypothalamus
↓ Releasing hormone (e.g. GHRH, TRH)
↓
Pituitary gland
↓ Trophic hormone (e.g. GH, TSH)
Endocrine gland
↓ Effector hormone (e.g. IGF-1, T4)
Target organ →Effect (e.g. growth, increased metabolic rate)
[Negative feedback control] inhibited by the endocrine hormone which exerts negative feedback effects on the____ to inhibit release of releasing and_____ hormones.
HPA
trophic
Negative feedback control diagram
Physiologic input from the brain
↓
Hypothalamus ⬅︎ inhibit
↓. Releasing hormone
Pituitary gland ⬅︎ inhibit
↓. Trophic hormone
Endocrine gland
↓. Effector hormone ⬆︎Neg feedback
Target organ⤍Effect
What inhibits growth hormone –> insulin-like growth factors
Somatostatin
Thyrotropin releasing hormone (TRH)
↓
Thyrotropin
↓
What effector hormones
Thyroxine (T4 & T3)
Hormone deficiency [hypothyroidism or type I diabetes:]
requires exogenous hormone replacement due to lack of endogenous production or receptor defect
Hormone excess [e.g. acromegaly (tumour): ]
requires endocrine surgery or inhibitors of hormone release or action to combat excess levels
Hormone supplementation [e.g. type II diabetes, or corticosteroid therapy for immune suppression: ]
exogenous hormone (or analogs) administered to amplify effect
Hormone suppression [pituitary suppression (for IVF) or contraception: ]
achieved by exogenous hormones to maintain negative feedback
Growth Hormone (GH) info (Choh Hao Li)
- secretion is stimulated by GHRH & inhibited by somatostatin
- secretion is also stimulated by deep sleep, especially in children
- secretion is highest in the newborn and during puberty, falling dramatically with adulthood and ageing
- 191 aa peptide, most abundant of the pituitary hormones
Effects of GH
- The major effect of GH is to stimulate normal proportional growth.
- It does this by stimulating the production by the liver of insulin-like growth factor-1 (IGF-1)
- IGF-1 (70 aa) stimulates protein synthesis (esp. in skeletal muscle), bone growth and cartilage synthesis
Effects of GH diagram
Hypothalamus
↓ (+) ↓ (-)
GHRH Somatostatin
↓
Anterior pituitary
↓
Growth hormone (somatropin)
↓ ↓
↓ Liver
↓ ↓
↓ IGF-1
↓
Muscle, bone, etc
Feedback on slide
______ which is identical to GH and produced by recombinant DNA technology
Somatropin
Control of GH levels
- Negative feedback mechanisms
– GH inhibits GHRH release
– IGF-1 inhibits GH release and stimulates somatostatin release - for tight control over GH and IGF-1 release (and actions)
- loss of this tight control of GH production can lead to
– lack of growth (dwarfism)
– excess growth
(giantism, acromegaly)
loss of this tight control of GH production can lead to
– lack of growth (dwarfism)
– excess growth
(giantism, acromegaly)
Growth Hormone Deficiency → Dwarfism
- Somatropin used to achieve satisfactory growth in dwarfism caused by low GH production
- not useful if dwarfism is caused by a lack of GH receptors - Laron dwarfism or lack of IGF-1 (African pygmies) – use human IGF-1 instead
Normal GH
Anterior pituitary
↓
Growth Hormone
↓ ↓
↓ Liver
↓ ↓
↓ IGF-1
↓
Normal growth
Hypopituitary dwarfism diagram due to pituitary gland tumor or genetic factors
↓ Anterior pituitary function
↓
↓ Growth Hormone
↓ ↓
↓ Liver
↓ ↓
↓ ↓ IGF-1
↓
Reduced growth
GH excess → Giantism / Acromegaly
E.g. Pituitary gland tumor
↑ Anterior pituitary function
↓
↑ Growth Hormone
↓
Liver
↓
↑ IGF-1
↓
Enhanced growth
Acromegaly
- generally caused by a benign pituitary tumour and increased GH
- enlargement mainly of the facial structures, and hands and feet
- ↑ death rate (av. life span<10 years) due to higher rates of cardiovascular & lung disease, diabetes, etc. (not cancer)
Overview of acromegaly treatment
- Surgery → ↓tumor
- Somatostatin Analogues → ↓GH release
- GH- receptor antagonist → ↓GH actions
- objective is to reduce IGF-1 levels, as elevated levels of IGF-1 are linked to higher death rates.
Treatment of Acromegaly [surgery]
- surgery = 1st line treatment (50% success rate)
– then radiation to remove lingering tumor cells (slow response) - if surgery is not effective then the release of GH & IGF-1 may be inhibited by somatostatin analogues
Treatment of Acromegaly [somatostatin analogues]
- if surgery not effective then the release of GH & IGF-1 inhibited by somatostatin analogues (60-80% success rate)
- octreotide/lanreotide (s.c. injection 2-3 times daily/ monthly)
- pasireotide (pan SST receptor agonist, ↑ response rate)
pasireotide
- somatostatin analog
- SST receptor agonist,
- inhibition of ACTH secretion (not on slide)
Treatment of Acromegaly [GH- rec antagonist]
- pegvisomant GH receptor antagonist (>90% success)
Growth hormone receptor activation
- GH is a 191 amino acid protein
- GH binds to 2 cell-surface GH receptors, resulting in receptor dimerization and activation (enzyme-linked receptor)
- GH receptor activation –> enhanced IGF-1 expression
GH receptor blockade (Pegvisomant)
- mutant GH molecule
- single amino acid substitution (Gly for Arg at position 120),
- aa disrupts the binding to the 2nd GH receptor & prevents GH receptor dimerization & activation.
- Pegvisomant (PEG) stops dimerisation → no receptor activation → No IGF-1 production
